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Crizotinib in ROS1-rearranged non-small-cell lung cancer
Alice T Shaw1, Sai-Hong I Ou, Yung-Jue Bang
1From the Massachusetts General Hospital Cancer Center (A.T.S., L.P.L., Z.Z., J.W.C., A.J.I.), Dana-Farber Cancer Institute (G.I.S.), and Beth Israel Deaconess Medical Center (D.B.C.) - all in Boston; University of California at Irvine, Irvine (S.-H.I.O.), and Pfizer Oncology, La Jolla (W.T., S.M.S., L.M.T., J.G.C., K.D.W.) - both in California; Seoul National University Hospital, Seoul, South Korea (Y.-J.B.); University of Colorado, Aurora (D.R.C., M.V.-G., R.C.D.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.); University of Chicago, Chicago (R.S.); Memorial Sloan Kettering Cancer Center, New York (G.J.R.); Karolinska Institutet, Stockholm (Z.Z.); and Rho, Chapel Hill, NC (P.S.).
Background:
Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.
Methods:
We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.
Results:
The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.
Conclusions:
In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Insights
Crizotinib demonstrated significant antitumor activity in patients with advanced ROS1-rearranged non-small-cell lung cancer (NSCLC). This finding establishes ROS1 rearrangement as a key biomarker for predicting response to crizotinib therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chromosomal rearrangements involving the ROS1 gene define a specific molecular subtype of non-small-cell lung cancer (NSCLC).
- These ROS1-rearranged NSCLCs are potentially susceptible to targeted therapy with ROS1 kinase inhibitors.
- Crizotinib is an established inhibitor of ALK, ROS1, and MET tyrosine kinases.
Purpose of the Study:
- To evaluate the safety and efficacy of crizotinib in patients with advanced NSCLC harboring ROS1 rearrangements.
- To assess the pharmacokinetic profile and response to crizotinib therapy in this patient population.
Main Methods:
- An expansion cohort of 50 patients with advanced NSCLC and confirmed ROS1 rearrangement was enrolled in a Phase 1 study.
- Patients received crizotinib at 250 mg orally twice daily.
- ROS1 fusion partners were identified using next-generation sequencing or RT-PCR; safety and response were assessed.
Main Results:
- An objective response rate of 72% was observed, including 3 complete and 33 partial responses.
- Median duration of response was 17.6 months, and median progression-free survival was 19.2 months.
- Seven ROS1 fusion partners were identified (5 known, 2 novel); no correlation between fusion type and response was found. Safety was consistent with previous studies.
Conclusions:
- Crizotinib exhibits significant antitumor activity in patients with advanced ROS1-rearranged NSCLC.
- ROS1 rearrangement identifies a distinct molecular subgroup of NSCLC highly responsive to crizotinib.
- Crizotinib represents a viable therapeutic option for this specific NSCLC molecular subtype.
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